A patient presents with a primary pancreatic tumor that has metastasized to the liver. The liver is completely infiltrated with metastasis, and ultimately the metastasis will prevent the liver from functioning, and death will ensue. This is a frustrating situation, because we know where the metastases are located, we can image them, and attempt to treat them with cytotoxic chemotherapy. Unfortunately, chemotherapy only inhibits the metastasis in a short-term manner, and rarely eradicates the disease.  Unlike chemotherapy, radiotherapy is highly effective in eradicating tumors, but it cannot be used to treat widespread metastasis in the liver due to normal tissue toxicity, especially at the doses of radiation needed to eliminate the metastasis. For radiotherapy to be used in such a manner, we need to develop effective radioprotectors that protect normal tissue, but not tumor tissue from radiation induced cell death. We have identified prolyl hydroxylase (PHD) inhibitors as promising agents that both stimulate erythropoiesis and protect the gastrointestinal tract from lethal doses of radiation without any effect on tumor radiosensitivity. Such agents will revolutionize the use of radiation for the treatment of metastasis, and most importantly would start to increase the long-term survival of patients with metastatic disease.  So, our big idea for the next ten years is the normal tissues from radiation-induced lethality. This is a completely different approach to the treatment of metastatic disease that is risky, but would be revolutionary. 

1. Rankin, E.B., Wu, C., Khatri, R., Wilson, T.L.S., Andersen, R., Araldi, E., Rankin, A.L. Yuan, J., Kuo, C.J., Schipani, E. and Giaccia, A.J.  The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO.  Cell 149:63-74, 2012 (PMCID: PMC3408231).
2. Taniguchi, C.M., Miao, Y.R., Diep, A.N., Wu, C., Rankin, E.B., Atwood, T.F. Xing, L., and Giaccia, A.J.  PHD inhibition mitigates and protects against radiation-induced gastrointestinal toxicity via HIF2. Sci Transl Med 6:236ra64, 2014 (PMCID: PMC4136475).
3. Giaccia, A.J.  Molecular Radiobiology: The State of the Art. J Clin Oncol 32:2871-2878, 2014.
4. Olcina, M.M. and Giaccia, A.J.  Reducing radiation-induced gastrointestinal toxicity – the role of the PHD/HIF axis.  J Clin Invest, in press.